The pediatric acenocoumarol dosing algorithm: The Children Anticoagulation and Pharmacogenetics Study

BACKGROUND: The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the right dose for a patient, however not for acenocoumarol.

OBJECTIVES: To develop dosing algorithms for pediatric patients on acenocoumarol with and without genetic information.

METHODS: The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as ≥3 consecutive International Normalized Ratio measurements within therapeutic range over a period of ≥3 weeks.

RESULTS: In total 175 patients were included in the study of whom 86 patients had a stable period and no missing clinical information (clinical cohort; median age 8.9 years and 49% female). Of 80 of these 86 patients genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. By adding the genotypes of VKORC1, CYP2C9, and CYP2C18 to the algorithm it increased to 61.8%.

CONCLUSIONS: These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability. This article is protected by copyright. All rights reserved.